Renal Ciliopathies: Sorting Out Therapeutic Approaches for Nephronophthisis

Abstract

Nephronophthisis (NPH) is an autosomal recessive ciliopathy and a major cause of end-stage renal disease in children. The main forms, juvenile and adult NPH, are characterized by tubulointerstitial fibrosis whereas the infantile form is more severe and characterized by cysts. NPH is caused by mutations in over 20 different genes, most of which encode components of the primary cilium, an organelle in which important cellular signaling pathways converge. Ciliary signal transduction plays a critical role in kidney development and tissue homeostasis, and disruption of ciliary signaling has been associated with cyst formation, epithelial cell dedifferentiation and kidney function decline. Drugs have been identified that target specific signaling pathways (for example cAMP/PKA, Hedgehog, and mTOR pathways) and rescue NPH phenotypes in in vitro and/or in vivo models. Despite identification of numerous candidate drugs in rodent models, there has been a lack of clinical trials and there is currently no therapy that halts disease progression in NPH patients. This review covers the most important findings of therapeutic approaches in NPH model systems to date, including hypothesis-driven therapies and untargeted drug screens, approached from the pathophysiology of NPH. Importantly, most animal models used in these studies represent the cystic infantile form of NPH, which is less prevalent than the juvenile form. It appears therefore important to develop new models relevant for juvenile/adult NPH. Alternative non-orthologous animal models and developments in patient-based in vitro model systems are discussed, as well as future directions in personalized therapy for NPH.

Keywords: cell cycle; ciliopathy; drug screen; gene therapy; hereditary kidney disease; nephronophthisis; signaling; therapy.

FIGURE 1

Composition of the primary cilium. (A) The mother centriole docks to the apical plasma membrane and forms the basal body which is connected to the plasma membrane by transition fibers. The basal body anchors the ciliary axoneme, consisting of 9+0 microtubule doublets. At the transition zone, Y-linkers connect the axoneme to the ciliary membrane. The transition zone functions as a gate through which membrane receptors and other proteins can enter the cilium. Intraflagellar transport (IFT) inside the cilium is mediated by kinesin-2 motors (anterograde transport) and dynein motors (retrograde transport). (B) NPH proteins localize to distinct functional compartments of the primary cilium. IFT proteins in pink are encoded by NPH-associated genes. No ciliary localization was demonstrated for ZNF423 and MAPKBP1.

FIGURE 2

Ciliary GPCR signaling. (A) The vasopressin receptor type 2 (V2R) is located in the ciliary membrane. When activated, signal transduction via Gs alpha subunit (Gαs) leads to increased production of cAMP by adenylate cyclase (AC) and subsequent activation of protein kinase A (PKA). PKA phosphorylates aquaporin 2 (AQP2), which translocates to the apical cell membrane leading to increased water reabsorption. In addition, PKA phosphorylates the cystic fibrosis transmembrane conductance regulator (CFTR), leading to transport of Cl^– ions and fluid secretion into the lumen, and CREB and STAT3, enhancing transcription. Other downstream effects include increased CDK signaling. Opening of the polycystin-1/polycystin-2 (PC1/PC2) complex in response to urine flow inhibits the cAMP/PKA pathway via inhibition of AC5/6 and through PDE4C. (B) Other main ciliary GPCRs are Smo and the constitutively active Shh receptor GPR161. In the absence of Shh, Ptch1 excludes and inhibits Smo, leading to repression of Gli transcription factors by SuFu, and GPR161 signaling leads to increased cAMP-dependent activation of PKA. Elevated PKA further represses Gli transcription factors. Binding of a Hh ligand leads to entry of Smo and consequent removal of GPR161 from the ciliary membrane, resulting in decreased cAMP/PKA activity and activation of Gli transcription factors.